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MYC antagonizes the differentiation induced by imatinib in chronic myeloid leukemia cells through downregulation of p27KIP1

Oncogene volume 32, pages 2239–2246 (2013)Cite this article

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Abstract

Chronic myeloid leukemia (CML) progresses from a chronic to a blastic phase where the leukemic cells are proliferative and undifferentiated. The CML is nowadays successfully treated with BCR-ABL kinase inhibitors as imatinib and dasatinib. In the CML-derived K562 cell line, low concentrations of imatinib induce proliferative arrest and erythroid differentiation. We found that imatinib upregulated the cell cycle inhibitor p27KIP1 (p27) in a time- and -concentration dependent manner, and that the extent of imatinib-mediated differentiation was severely decreased in cells with depleted p27. MYC (c-Myc) is a transcription factor frequently deregulated in human cancer. MYC is overexpressed in untreated CML and is associated to poor response to imatinib. Using K562 sublines with conditional MYC expression (induced by Zn2+ or activated by 4-hydroxy-tamoxifen) we show that MYC prevented the erythroid differentiation induced by imatinib and dasatinib. The differentiation inhibition is not due to increased proliferation of MYC-expressing clones or enhanced apoptosis of differentiated cells. As p27 overexpression is reported to induce erythroid differentiation in K562, we explored the effect of MYC on imatinib-dependent induction of p27. We show that MYC abrogated the imatinib-induced upregulation of p27 concomitantly with the differentiation inhibition, suggesting that MYC inhibits differentiation by antagonizing the imatinib-mediated upregulation of p27. This effect occurs mainly by p27 protein destabilization. This was in part due to MYC-dependent induction of SKP2, a component of the ubiquitin ligase complex that targets p27 for degradation. The results suggest that, although MYC deregulation does not directly confer resistance to imatinib, it might be a factor that contributes to progression of CML through the inhibition of differentiation.

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Acknowledgements

We thank Pilar Frade, María Aramburu and Guillermo Santana for technical assistance, Robert Eisenman, Theodore Lee and Robert Sclafani for constructs, and M Teresa Molero and Carlos Richard for useful comments on the manuscript. Funding for this work was provided by grants SAF11-23796 and ISCIII-RETIC RD06/0020/0017 to JL, FIS 11/00397 to MDD, SAF09-09254 and Fundación Mutua Madrileña to JMP, FIS08-0878 to SA and FIS08-0440 to JCC.

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Author notes

  1. N Ferrándiz & J P Vaqué

    Present address: 5Current address: MRC Clinical Sciences Centre, Imperial College Faculty of Medicine Hammersmith Hospital Campus, London, UK,

  2. Current address: IFIMAV, Santander, Spain

Authors and Affiliations

  1. Servicio de Hematología and Unidad de Investigación, Hospital Universitario Dr Negrín, Las Palmas, Spain

    M T Gómez-Casares & C E López-Jorge

  2. Departamento de Biología Molecular, Group of Transcriptional Control and Cancer, Facultad de Medicina, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Universidad de Cantabria-CSIC-SODERCAN, Santander, Spain

    E García-Alegria, N Ferrándiz, R Blanco, J P Vaqué, G Bretones, J M Caraballo, M D Delgado & J León

  3. Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

    S Alvarez & J C Cigudosa

  4. Instituto de Investigaciones Biomédicas Alberto Sols, CSIC, Madrid, Spain

    P Sánchez-Bailón & J Martín-Perez

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Gómez-Casares, M., García-Alegria, E., López-Jorge, C. et al. MYC antagonizes the differentiation induced by imatinib in chronic myeloid leukemia cells through downregulation of p27KIP1. Oncogene 32, 2239–2246 (2013). https://doi.org/10.1038/onc.2012.246

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